Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
  • C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention generally relates to the field of pharmaceutical chemistry. More particularly, the present invention relates to novel vinblastine derivatives, the preparation and use thereof and pharmaceutical compositions comprising the same.
• the vinblastine derivatives show inhibiting activities against tumor cell lines, and can be used as medicaments for treating malignant tumors.
• Tumor is one of the malignant diseases that threaten human health. Every year, more than 5,000,000 peoples die for tumors throughout the world. In China, more than 1,600,000 peoples are newly found to be sufferring from tumors and the peoples died for them have exceeded 1,300,000 each year. Hence, it has been a worldwide focus to develop anti-cancer medicaments.
• Vinca alkaloids anti-tumor agents are a type of bisindole alkaloids having anti-cancer activities. They are isolated from Catharanthus roseus (L.) G. Don and Catharanthus roseus (L.) G Don cv. Flavus which are perivinkle plants of Apocynaceae family. Natural Vinca alkaloids can be biosynthesized through coupling catharanthine and vindoline, which are mono-indole alkaloids rich in the plants.
• Vinca alkaloids or derivatives thereof in clinical use i.e., vinblastine (VLB), vincristine (VCR), vindesine (VDS) and vinorelbine (NVB).
• VLB vinblastine
• VCR vincristine
• VDS vindesine
• NVB vinorelbine
• Vinca alkaloids anti-tumor agents are cell cycle specific agents that mainly function in the G2 phase (post-synthetic phase of DNA) of tumor cells. It is reported that the mechanism of action of Vinca alkaloids anti-tumor agents are that they bind with tubulin inhibiting the formation of microtubules from the polymerization of tublin dimers, and also induce the disruption of the cytoskeleton blocking the formation of mitotic spindles and arresting the tumor cell divison and proliferation at mitotic metaphase, and thus exhibit the antineoplastic activity ( R.J. Owellen and C.A.
• the tubulin binding affinity of Vinca alkaloids anti-tumor agents has a poorly linear correlation with their inhibiting activities against cell growth. It is generally considered that the differences of the activities and side effects among Vinca alkaloids anti-tumor agents are mainly resulted from the differences of their uptake and retention in tumor tissues.
• a small change in the structure of a vinblastine analog may cause great variation in its anti-tumor spectra and toxicity and side effect spectra.
• vinblastine and vincristine are identical to a N-methyl group and a N-aldehyde group.
• vincristine exhits good inhibiting activity against Rhabdoid Tumors in vivo, and vinblastine shows no efficacy.
• they are completely different in their toxicity spectra.
• the major toxiticies are peripheral neurotoxicity for vincristine and anaemia and reduction of leucocyte for vinblastine ( N. Bruchovsky et al., Cancer Res. 1965, 25, 1232-1238 ).
• Vinorelbine has a poorer inhibiting activity on P388 and L1210 cell lines than vinblastine and vincristine, but a better inhibiting activity on lung cancer than other vinblastine analogs. Therefore, it has been a first-line agent for treating clinically nonsmall-cell lung cancers ( S.Cros, el al., Seminars in Oncology, 1989, 16, 15-20 ).
• the present inventors have found novel vinblastine derivatives with strong anti-tumor activity through synthesizing a series of vinblastine analogs by coupling a modified vindoline with a catharanthine, followed by evalutated in vivo and in vitro.
• the present invention is proposed and made to solve the above mentioned problems.
• One object of the present invention is to provide a class of novel vinblastine derivatives with anti-tumor activity.
• Another object of the present invention is to provide a process to prepare the above vinblastine derivatives.
• Another object of the present invention is to provide phamaceutical compositions comprising the above vinblastine derivatives.
• Another object of the present invention is to provide uses of the above vinblastine derivatives and the compositions comprising the same.
• physiologically acceptable salts refer to physiologically acceptable salts formed by the derivatives of the invention with various acids, wherein the acids include organic or inorganic acids, for example, hydrochloric acid, sulphuric acid, phosphonic acid, acetic acid, tartaric acid, benzoic acid, maleic acid, succinic acid, citric acid, etc.
• a vinblastine derivative according to the invention has a structure represented by one of the following formulas BM1-BM80,
• the present invention further provides a method for preparing the above vinblastine derivatives, which comprises:
• the solvent used in the alkylations is selected from the group consisting of dichlormethane, chloroform and tetrahydrofuran
• the phase transfer catalyst used in the alkylations is selected from the group consisting of tetrabutylammonium iodide and tetrabutylammonium bromide
• the temperature for the alkylations may be in the range from 0 °C to room temperature or in the range from 50 °C to 100 °C depended on the reaction conditions necessary for a specific compound.
• the catalyst is selected from the group consisting of triethylamine, diisopropyl ethyl amine, pyridine and 4-(N,N-dimethyl)aminopyridine (DMAP) in the acylation
• the acylating agent is selected from the group consisting of an anhydride, an acyl chloride, a ligand formed from an anhydride and thiazolidine-2-thione (or benzotriazole) and a ligand formed from an acyl chloride and thiazolidine-2-thione in the acylation.
• the catalyst is selected from the group consisting of sodium hydride, triethylamine, diisopropyl ethyl amine, pyridine or 4-(N,N-dimethyl)aminopyridine (DMAP), and the raw material is selected from the group consisting of an isocyanate and a ligand formed from an amine and a carbonyl diimidazole (CDI) during the synthesis of intermediate compound D.
• DMAP 4-(N,N-dimethyl)aminopyridine
• the catalyst is selected from the group consisting of triethylamine, diisopropylethylamine (DIPEA), pyridine or 4-(N,N-dimethyl)aminopyridine (DMAP), and the raw material is selected from the group consisting of a chloroformate and a chloroformate synthesized from an alcohol and solid phosgene during the synthesis of intermediate compound F.
• DIPEA diisopropylethylamine
• DMAP 4-(N,N-dimethyl)aminopyridine
• the intermediate compound A is prepared by the reduction of vindoline which is used as the raw material, and then epoxidized, azidized and reduced to form intermediate compound B.
• Intermediate compounds C to F can be synthesized respectively by furnishing the structure of the intermediate compound A or B with a series of reactions such as alkylation or acylation.
• the vinblastine derivatives of the invention are thereafter produced by coupling the intermediate compounds C to F with catharanthine respectively, or by further reduction, alkylation, acylation, or fluoration of the coupled products.
• TLC Thin-layer chromatography
• reaction mixture is extracted with organic solvents such as ethyl acetate, dichlormethane (DCM) and chloroform. Then the combined organic phase is washed sequently with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate or anhydrous sodium sulfate, and concentrated at a low temperature under a reduced pressure to remove the solvent.
• organic solvents such as ethyl acetate, dichlormethane (DCM) and chloroform.
• Vindoline was reduced by lithium-aluminum hydride (LiAlH 4 ) in tetrahydrofunan to provide intermediate compound A.
• the intermediate compound A was treated with p-toluene sulfonylchloride under a basic condition to give an epoxide, which was thereafter subjected to a ring-opening reaction with sodium azide, followed by reduction with LiAlH 4 in tetrahydrofunan to obtain the intermediate compound B.
• the synthetic routes for intermediate compounds C to F are as follows, wherein the compound A or B is used as a raw material.
• the compound A was dissolved in dichloromethane, chloroform or tetrahydrofunan, followed by addition of a 50% sodium hydroxide solution.
• the reaction mixture was treated with alkylating agents such as halogenated hydrocarbon and epoxide in the presence of a phase transfer catalyst such as tetrabutylammonium iodide or tetrabutylammonium bromide at a reaction temperature from 0 °C to room temperature or from 50 °C to 100 °C to give a dialkyl substituted product C, or a monoalkyl substituted product which was then treated with anhydride, acyl chloride in the presence of a base such as triethylamine, diisopropyl ethyl amine, pyridine or 4-(N,N-dimethyl amino)pyridine to provide product C.
• the compound A was directly treated with an anhydride or an acyl chloride in the presence of a base to obtain di-acylated product
• Procedure 1 An amine was dissolved in dichloromethane or tetrahydrofunan under argon atmosphere, followed by addition of an appropriate amount of a base (triethylamine, diisopropyl ethyl amine, pyridine or 4-(N,N-dimethyl)aminopyridine). To the reaction mixture, a solution of solid phosgene in dichloromethane or tetrahydrofunan was slowly added dropwisely under ice bath, then the reaction was allowed to react for half an hour under ice bath and then for a few hours at room temperature to obtain an isocyanate.
• a base triethylamine, diisopropyl ethyl amine, pyridine or 4-(N,N-dimethyl)aminopyridine.
• Procedure 2 An amine was dissolved in dichloromethane or tetrahydrofunan under argon atmosphere, followed by addition of an appropriate amount of a base (triethylamine, diisopropyl ethyl amine, pyridine or 4-(N,N-dimethyl)aminopyridine). Then carbonyl diimidazole was added therein. After reacted for 24 hours at room temperature, the reaction mixture was evaporated to dryness to obtain an intermediate, which was then added into a solution of sodium hydride and compound A in tetrahydrofunan. The reaction mixture was allowed to react for 8 hours at room temperature.
• a base triethylamine, diisopropyl ethyl amine, pyridine or 4-(N,N-dimethyl)aminopyridine.
• Compound B was dissolved in dichloromethane or chloroform, and treated with anhydride or acyl chloride in the presence of a base (triethylamine, diisopropyl ethyl amine, pyridine or 4-(N,N-dimethyl) amino pyridine) to obtain di-acylated product E, or directly alkylated with an alkylating agent such as a halogenated hydrocarbon or an epoxide to obtain mono- or di-alkylated product E.
• a base triethylamine, diisopropyl ethyl amine, pyridine or 4-(N,N-dimethyl) amino pyridine
• an alkylating agent such as a halogenated hydrocarbon or an epoxide
• compound B was dissolved in tetrahydrofunan, followed by addition of sodium hydride and ligand III (N-acylthiazolidine-2-thione) under argon atmosphere to react to give a monoacylated product, which was then treated with an anhydride or an acyl chloride to obtain di-isoacylated product E.
• sodium hydride and ligand III N-acylthiazolidine-2-thione
• a Heterocyclic compound of thiazolidine-2-thione II was dissolved in dichloromethane or chloroform, and treated with an anhydride or an acyl chloride in the presence of a base (triethylamine, diisopropyl ethyl amine, pyridine or 4-(N,N-dimethyl)aminopyridine) to obtain ligand III (N-acylthiazolidine-2-thione).
• a base triethylamine, diisopropyl ethyl amine, pyridine or 4-(N,N-dimethyl)aminopyridine
• Fluoridization was carried out at -40 °C for 1 hour in anhydrous fluohydric acid using antimonium(V) fluoride as a catalyst to obtain compound BM' with a yield of about 40% ( J. Fahy etc., J. Am. Chem. Soc. 1997, 119, 8567 ).
• the invention also provides a composition comprising a therapeutically effective amount of the above vinblastine derivative or physiologically acceptable salt thereof.
• the invention further provides uses of the above vinblastine derivative or physiologically acceptable salt thereof in preparing medicaments for treating tumors.
• the invention still further provides a pharmaceutical composition for treating tumors, which comprises the above vinblastine derivative or physiologically acceptable salt thereof as an active component.
• a series of novel vinblastine derivatives were designed and synthesized in the present invention.
• the compounds have good inhibiting activities against tumor cell lines such as human lung cancer cell line (A-549) and human cervical carcinoma cell line (Hela), and thus can be used to prepare medicaments for treating malignant tumors.
• the compounds of the invention are synthesized simply and easily, and the raw materials thereof are rich.
• silica gel is GF 254 with a particle size of 200-300 mesh, which is commercially available form Qingdao Haiyang Chemical Co. Ltd or Yantai Yuanbo Silica Gel Co.
• reaction mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain an epoxide as an oily intermediate, which was used in the next step without purification.
• the combined organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a concentrate.
• the concentrate was dissolved in 1 mL of pyridine under argon atmosphere, followed by addition of 1 mL of acetic anhydride. After 8 h of stirring at room temperature, 30 mL of ethyl acetate and 10 mL of saturated sodium bicarbonate solution were added thereto and the stirring continued for 2 minutes.
• the combined organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a concentrate.
• the concentrate was dissolved in 1 mL of pyridine under argon atmosphere, followed by addition of 1 mL of acetic anhydride. After 8 h of stirring at room temperature, 30 mL of ethyl acetate and 10 mL of saturated sodium bicarbonate solution were added thereto and the stirring continued for 2 minutes.
• the combined organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a concentrate.
• the combined organic phase was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a concentrate.
• the concentrate was dissolved in 1 mL of pyridine under argon atmosphere, followed by addition of 1 mL of acetic anhydride. After 8 h of stirring at room temperature, 30 mL of ethyl acetate and 10 mL of saturated sodium bicarbonate solution were added, and the stirring continued for 10 minutes.
• the compound A (1.0 mmol) and 3-propionyl-thiazolidine-2-thione (1.1 mmol) were dissolved in 10 mL of tetrahydrofunan, followed by addition of sodium hydride (60%, 1 mmol) under argon atmosphere. After stirred for 1-4 h at room temperature, the reaction micture was washed with 1 mL of saturated ammonium chloride solution and extracted with chloroform. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was dissolved in 1 mL of pyridine under argon atmosphere, followed by addition of 1 mL of acetic anhydride.
• reaction mixture was extracted with methylene chloride (20 mL ⁇ 4), and the methylene chloride layer was washed with saturated salt solution (20 mL ⁇ 3), filtered with Celite and concentrated under reduced pressure at a low temperature.
• the concentrate was dissolved in 2 mL of methanol and the solution was left for 2 minutes. A white crystal was crystallized, filtered and dried to give 257 mg of compound BM1 in 56% yield.
• Compound BM2 was prepared as a white powder following the procedure for preparing compound BM1.
• Compound BM3 was prepared as a white powder following the procedure for preparing compound BM1.
• Compound BM4 was prepared as a white powder following the procedure for preparing compound BM1.
• Compound BM5 was prepared as a white powder in 63% yield following the procedure for preparing compound BM1.
• reaction mixture was extracted with methylene chloride (40 mL ⁇ 4), and the methylene chloride layer was washed with saturated salt solution (20 mL ⁇ 3), filtered with Celite and concentrated under reduced pressure at low temperature. After the concentrate was dissolved in 2 mL of methanol and the solution was left for 2 minutes, a white crystal was crystallized, filtered and dried to give 475 mg of compound BM6 in 60% yield.
• Compound BM10 was prepared as a white power following the procedure for preparing compound BM6.
• Compound BM11 was prepared as a white powder following the procedure for preparing compound BM6.
• reaction mixture was extracted with methylene chloride (40 mL ⁇ 4), and the methylene chloride layer was washed with saturated salt solution (20 mL ⁇ 3), filtered through Celite and concentrated under reduced pressure at low temperature. After the concentrate was dissolved in 2 mL of methanol and the solution was left for 2 minutes, a white crystal was crystallized, filtered and dried to give 158 mg of compound BM12 in 48% yield.
• Compound BM13 was prepared as a white powder following the procedure for preparing compound BM6.
• Compound BM14 was prepared as a white powder following the procedure for preparing compound BM6.
• Compound BM15 was prepared as a white powder in 60% yield following the procedure for preparing compound BM6.
• Compound BM16 was prepared as a white powder following the procedure for preparing compound BM6.
• Compound BM17 was prepared as a white powder following the procedure for preparing compound BM6.
• Compound BM18 was prepared as a white powder following the procedure for preparing compound BM6.
• Compound BM19 was prepared as a white powder following the procedure for preparing compound BM6.
• Compound BM20 was prepared as a white powder following the procedure for preparing compound BM6.
• Compound BM21 was prepared as a white powder following the procedure for preparing compound BM6.
• Compound BM22 was prepared as a white powder following the procedure for preparing compound BM6.
• Compound BM23 was prepared as a white powder following the procedure for preparing compound BM6.
• Compound BM24 was prepared as a white powder following the procedure for preparing compound BM6.
• reaction mixture was then extracted with methylene chloride (20 mL ⁇ 4), and the methylene chloride layer was washed with saturated salt solution (20 mL ⁇ 3), filtered through Celite and concentrated under reduced pressure at low temperature. After the concentrate was dissolved in 2 mL of methanol and the solution was left for 2 minutes, a white crystal was crystallized, filtered and dried to give 233 mg of compound BM25 in 50% yield.
• Compound BM26 was prepared following the procedure for preparing compound BM25.
• Compound BM27 was prepared following the procedure for preparing compound BM25.
• Compound BM28 was prepared following the procedure for preparing compound BM25.
• Compound BM29 was prepared following the procedure for preparing compound BM25.
• Compound BM30 was prepared following the procedure for preparing compound BM25.
• Compound BM31 was prepared following the procedure for preparing compound BM25.
• Compound BM32 was prepared following the procedure for preparing compound BM25.
• Compound BM33 was prepared following the procedure for preparing compound BM25.
• Compound BM34 was prepared following the procedure for preparing compound BM25.
• Compound BM35 was prepared following the procedure for preparing compound BM25.
• Compound BM36 was prepared following the procedure for preparing compound BM25.
• Compound BM37 was prepared following the procedure for preparing compound BM25.
• Compound BM38 was prepared following the procedure for preparing compound BM25.
• Compound BM39 was prepared following the procedure for preparing compound BM25.
• Compound BM40 was prepared following the procedure for preparing compound BM25.
• Compound BM41 was prepared following the procedure for preparing compound BM25.
• Compound BM42 was prepared following the procedure for preparing compound BM25.
• Compound BM43 was prepared following the procedure for preparing compound BM25.
• Compound BM44 was prepared following the procedure for preparing compound BM25.
• Compound BM45 was prepared following the procedure for preparing compound BM25.
• Compound BM46 was prepared following the procedure for preparing compound BM25.
• Compound BM47 was prepared following the procedure for preparing compound BM25.
• Compound BM48 was prepared following the procedure for preparing compound BM25.
• Compound BM49 was prepared following the procedure for preparing compound BM25.
• Compound BM50 was prepared following the procedure for preparing compound BM25.
• Compound BM51 was prepared following the procedure for preparing compound BM25.
• Compound BM52 was prepared following the procedure for preparing compound BM25.
• Compound BM53 was prepared following the procedure for preparing compound BM25.
• Compound BM54 was prepared following the procedure for preparing compound BM25.
• Compound BM55 was prepared following the procedure for preparing compound BM25.
• Compound BM56 was prepared following the procedure for preparing compound BM25.
• Compound BM57 was prepared following the procedure for preparing compound BM25.
• Compound BM58 was prepared following the procedure for preparing compound BM25.
• Compound BM59 was prepared following the procedure for preparing compound BM25.
• Compound BM60 was prepared following the procedure for preparing compound BM25.
• Compound BM61 was prepared following the procedure for preparing compound BM25.
• Compound BM62 was prepared following the procedure for preparing compound BM25.
• Compound BM63 was prepared following the procedure for preparing compound BM25.
• Compound BM64 was prepared following the procedure for preparing compound BM25.
• Compound BM65 was prepared following the procedure for preparing compound BM25.
• Compound BM66 was prepared following the procedure for preparing compound BM25.
• Compound BM67 was prepared following the procedure for preparing compound BM25.
• Compound BM68 was prepared following the procedure for preparing compound BM25.
• Compound BM69 was prepared following the procedure for preparing compound BM25.
• Compound BM70 was prepared following the procedure for preparing compound BM25.
• Compound BM71 was prepared following the procedure for preparing compound BM25.
• Compound BM72 was prepared following the procedure for preparing compound BM25.
• Compound BM73 was prepared following the procedure for preparing compound BM25.
• Compound BM74 was prepared following the procedure for preparing compound BM25.
• reaction mixture was slowly poured into a mixture containing 200 mL of ice water, 63.6 g (0.6 mol) of sodium carbonate and 30 mL of methylene chloride, and extracted with methylene chloride (50 mL ⁇ 2).
• Compound BM76 was prepared following the procedure for preparing compound BM75.
• Compound BM77 was prepared following the procedure for preparing compound BM75.
• Compound BM78 was prepared following the procedure for preparing compound BM75.
• Compound BM79 was prepared following the procedure for preparing compound BM75.
• Compound BM80 was prepared following the procedure for preparing compound BM75.
• the other vinblastine derivatives and physiologically acceptable salts thereof can also be prepared with reference to the above preparation examples for preparting vinblastine derivatives in combination with the prior art in the field.
• Human non-small cell lung cancer cell line A-549 was obtained from American Type Culture Collection, and human cervical carcinoma cell line Hela was from the Cell Bank of Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
• VLB vinblastine sulfate
• AVLB anhydrovinblastine tartrate
• NRB vinorelbine tartrate
• the tested compounds and positive controls were diluted with normal saline to a series of solutions with concentration gradients of 10 -4 M, 10 -5 M, 10 -6 M, 10 -7 M and 10 -8 M.
• SRB Sulforhodamine B Assay: human nonsmall-cell lung cancer cell line A-549 and human cervical carcinoma cell line Hela.
• tumor cells in the log phase of growth were seeded into 96-well microculture plates at 100 ⁇ L per well, and allowed to attach for 24 hours, followed by addition of a test compound or positive control at 10 ⁇ L per well.
• the test was carried out in triplicate wells, and included control wells containing the aqueous medium of normal saline as negative controls and a blank well containing all medium without cells for zeroing.
• the culture medium RPMI-1640
• the cells were then washed with distilled water for 5 times, dried in the air, followed by addition of a solution of SRB (Sigma) (4 mg/mL) in 1% glacial acetic acid at 100 ⁇ L per well. The cells were stained for 15 minutes at room temperature, and the supernatant was discarded. The plates were washed for 5 times with 1% acetic acid, and dried in air. Finally, Tris solution was added at 150 ⁇ L per well, and the absorbance (A) was measured at a wavelength of 515 nm on a microplate reader.
• SRB Sigma
• Tris solution was added at 150 ⁇ L per well, and the absorbance (A) was measured at a wavelength of 515 nm on a microplate reader.
• Growth Inhibition % Absorbance of negative control - Absorbance of blank - Absorbance of sample - Absorbance of blank / Absorbance of negative control - Absorbance of blank ⁇ 100 %
• Drug concentration 10 ⁇ M, 1 ⁇ M, 0.1 ⁇ M, 10 nM, 1 nM, 0.1 nM
• IC 50 was fitted with GraphPad Prism 4. Table 1. The Cytotoxic activity against human lung cancer cell line A-549 and human cervical carcinoma cell line Hela of the tested samples (Ditartrate of all compounds were used in bioassays) Compound A549 (IC 50 , nM) Hela (IC 50 , nM) Vinblastine sulfate 3.4 2.5 Vinorelbine tartrate 23.1 9.1 Vincristine sufate 25.1 11.3 Anhydrovinblastine tartrate 60.2 40.2 BM1 348.3 154.0 BM2 440.7 113.4 BM3 >1000 >1000 BM4 >1000 295.4 BM5 >1000 286.3 BM6 124.0 47.6 BM10 709.8 637 BM11 >1000 >1000 BM12 575.7 95.9 BM13 >1000 >1000 BM14 >1000 >1000 BM15 >1000 227.5 BM22 >1000 >1000 BM23 >1000 >1000 BM24 >1000 >1000 BM25 >1000 476.7 BM26 56.3 61.6 BM
• the vinblastine derivatives of the present invention have the activities to inhibit the tumor cell proliferation, and a few of them have better inhibiting efficacy than that of vinorelbine tartrate (NVB) and anhydrovinblastine tartrate (AVLB) which are the positive controls.
• the vinblastine derivatives BM27, BM33, BM47, BM48, BM53 and BM57 which show excellent cell-based efficacy were further selected as examples to perform the following pharmacodynamics assays in vivo.
• mice Seven-weeks-old specific pathogen free (SPF) KM mice (weight, 18-22 g) were available from Shanghai Laboratory Animal Center, Chinese Academy of Sciences (Certicate code: SCXK (Shanghai) 2003-0003). Female KM mice were used to study inhibition of tumor growth in vivo. 7-1 days S 180 cells which were well-grown were dispersed into a suspension of about 2.5 ⁇ 10 6 /ml, and subcutaneously implanted into the axilla of mice. The animals were grouped randomly (d0). The compounds were administrated intravenously ( iv ) at d1 or d1 and d4.
• SPPF pathogen free mice
• Vinflunine (VFL), a vinblastine derivative with broad spectrum, low-toxicity and higher therapeutic index, was developed in the Pierre Fabre Laboratoires by application of superacid chemistry into modification of the structure of vinblastine. Under a strong acidic condition, C20', the inactive site of vinorelbine, is introduced two fluorine atoms, and the double bond between C3' and C4' is reduced into a single bond. VFL has an in vitro activity depending on its concentration and action time, and an IC 50 in the range of about 60-300 nM, which is lower than that of NVB by one order of magnitude or more. However, further animal tests showed that it had a lower toxicity and a higher therapeutic index.
• VFL is superior than vinorelbine in respect to their efficacy, tolerance and activity-range.
• the phase III of clinical study is in progress.
• vinblastine derivatives BM75, BM76, BM78, BM79 and BM80 were prepared respectively by fluoridation of vinblastine derivatives BM6, BM14, BM27, BM48 and BM53 having strong activities in vivo and in vitro, and assayed in respect to their in vivo antitumor activity.
• the result showed that vinblastine derivative BM78 has strong antitumor activity in vivo.
• SPF Specific pathogen free
• BALB/cA-nude mice were available from Shanghai SLAC Laboratory Animal CO. LTD (Certicate code: SCXK (Shanghai) 2004-0005).
• Human non-small cell lung cacer (A549) cells were subcutaneously implanted into the axilla of the nude mice. After the tumor grows to 100-300 mm 3 , the animals were grouped randomly (d0). The doses were 1.5 mg/kg, 3.0 mg/kg and 6.0 mg/kg for BM48 tartrate, and 10 mg/kg for vinorelbine tartrate. Both BM48 tartrate and vinorelbine tartrate were delivered intravenously.
• the BM48 tartrate was administrated at d0 once, and vinorelbine tartratewas delivered twice at d0 and d4 respectively.
• the tumor volumn and mice weights were measured 2-3 times each week, and the data were recorded.

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